Clinical Trial of the Efficacy and Safety of Raphamin in Prevention of Recurrences of Chronic Bacterial Cystitis

Trial design: double blind, placebo-controlled, randomized in parallel groups clinical trial.

The trial includes female outpatients aged 18 years or older with typical symptoms of chronic bacterial cystitis. The severity of typical symptoms of recurrence (exacerbation) should be 7 points or more according to the subscale "Typical symptoms" of the scale "Acute Cystitis Symptom Scale" (ACSS).

At Visit 1 (Day 1), after signing the patient information sheet and the informed consent form for participation in the clinical trial, complaints and medical history are collected, a physical examination is performed, and the severity of typical symptoms of cystitis is assessed using ACSS, collection of urine biosamples for urine analysis with microscopy and bacteriological examination (for identification the sensitivity of microorganisms to antibiotics), ultrasound examination of the urinary system (kidneys, bladder), and concomitant therapy is recorded.

Urinalysis, general and biochemical blood tests are planned in at least 190 patients.

If the patient meets inclusion criteria and does not meets exclusion inclusion criteria at Visit 1 (Day 1), the patient is randomized to one of two groups: patients of Group 1 take Phosphomycin (3 g once) and Raphamin according to the therapeutic and preventive regimen for 10 days; patients of Group 2 use Phosphomycin (3 g once) and Placebo according to the Raphamin regimen for 10 days.

If there is no effect from treatment within 48 hours or phosphomycin-resistant strains are detected, the physician conducts unscheduled visit and gives the patient an alternative drug Cefixime (400 mg). Cefixime is taken 1 times a day at a dose of 400 mg for 5 days or more (the duration of the course is determined by the physician).

All patients are provided with Phosphomycin, if resistance to it is detected - with alternative antibiotic Cefixime.

If microorganisms resistant to both Phosphomycin and Cefixime are detected, the patient is excluded from the trial, and the physician prescribes a treatment strategy in accordance with current standards.

In Electronic Patient Diary (EPD) the patient records the severity of typical cystitis symptoms using ACSS once a day at approximately the same time. Symptoms are recorded in the EPD from the patient's enrollment until Visit 2 (within 10 days of study drug administration), as well as during 10 days of treatment for each subsequent relapse (exacerbation).

In addition, any possible deterioration of the patient's condition (if applicable) is recorded in EDP to assess safety and record adverse events. The study physician instructs patients to complete the diary.

The first ACSS marks in the EDP are made by patient together with physician at Visit 1. EDP is available for filling throughout the patient's participation in the study. Once a week, the patients get SMS reminder: "If you have symptoms of the disease, enter them in the diary and contact the study physician. Don't forget to take your medication." In total, patient's follow-up lasts for 24 weeks. In the process of treatment and observation, 4 visits are scheduled: at day 1 (Visit 1) and day 11 (Visit 2), then at weeks 12 and 24 (Visits 3, 4). Visits 1, 2 and 4 are face-to-face (patient visits trial site); physician conducts physical examination, records symptoms and concomitant therapy, and checks the EPD. At Visit 2 (Day 11+3), the physician gives Phosphomycin/Cefixime and a study drug to patient, to treat a possible subsequent recurrence of cystitis. Blood and urine biosamples are taken from the patient who signed the ICF for taking biological samples (for safety assessment). The study drug received by the patient at Visit 1 should be returned to assess the patient's adherence to the study treatment. Phosphomycin/Cefixime also returns.

Visit 3 (Week 12 ± 3 days) is conducted by correspondence (telephone), in order to interview the patient about her condition.

In case of new recurrence of cystitis, patient contacts with trial physician by phone. On the basis of complaints and symptoms, physician makes conclusion about the onset of chronic cystitis recurrence. Patient completes ACSS in EPD. For a recurrence of cystitis, patient takes Phosphomycin (or Cefixime) and trial product (Raphamin/Placebo for 10 days). At the end of 10 days of treatment, an unscheduled face-to-face visit takes place (Day 11+3 days after the onset of recurrence), at which the patient returns the trial product and Phosphomycin/Cefixime, then the physician dispenses a new pack of trial product and Phosphomycin (or Cefixime) to treat a possible new recurrence of cystitis.

Visit 4 (Week 24 ± 3 days) is the final one; complaints are assessed, the patient undergoes a physical examination, returns the trial product and fills in a visual analogue scale (VAS), which assesses the degree of patient satisfaction with the therapy.

Inclusion criteria

• Female patients aged 18 years and older.
• Patients with a confirmed diagnosis of chronic bacterial cystitis.
• Patients with exacerbation of chronic cystitis based on typical symptoms of exacerbation of the disease with a severity of 7 points or more in accordance wuth ACSS.
• The first 48 hours from the onset of exacerbation) of chronic bacterial cystitis.
• Patients who agreed to use an acceptable method of contraception during the study (for women of reproductive potential).
• Availability of a signed patient information sheet and informed consent form for participation in the clinical trial.

Exclusion criteria

• Presence of urolithiasis, urinary tract obstruction, urothelial cancer, pelvic organ prolapse, neurogenic bladder disorders at the time of examination.
• Presence of malignant neoplasms of the urinary tract, ureter stone, more than 50 ml of residual urine in the bladder, confirmed by ultrasound examination.
• Suspicion of bladder tuberculosis.
• Presence of indications for hospitalization due to a serious condition, macrohematuria, complicated cystitis.
• Decompensation of diabetes mellitus, immunodeficiency of any etiology, malignant cancer of any localization, severe circulatory insufficiency (cardiovascular disease with functional class IV according to the classification of the New York Heart Association, 1964).
• Unstable angina pectoris or myocardial infarction within the previous 6 months.
• Chronic kidney disease (classes С3-5 А3).
• Hepatic impairment (Child-Pugh class C).
• Patients who require medicinal products prohibited for use in this study.
• Exacerbation or decompensation of chronic conditions affecting the patient's ability to participate in the clinical trial.
• Malabsorption syndrome, including congenital or acquired lactase deficiency or other disaccharidase insufficiency, galactosemia.
• Hypersensitivity to any component of the medicinal products used in the treatment.
• Pregnancy, breastfeeding; childbirth less than 3 months prior to study enrollment, unwillingness to comply with contraceptive methods during the study.
• The medications listed in the Prohibited Concomitant Medication section were administered within 4 weeks prior to enrollment.
• Patients who, from the investigator's point of view, will not comply with the observation requirements of the study or comply with the administration of the study drug.
• History of mental diseases, alcoholism, or drug abuse that, in the investigator's opinion, may interfere with the successful completion of trial procedures.
• Participation in other clinical trials within 3 months prior to enrollment.
• The patient belongs to the investigational site personnel directly involved in the study, closest relatives of the investigator. The closest relatives are defined as spouse, parents, children or siblings, regardless of whether they are natural or adopted.
• The patient works for the company OOO "NPF "MATERIA MEDICA HOLDING", being an employee of the company, a temporary contract worker or an appointed official responsible for performing the trial, or their close relative.